Forkhead box O's potential therapeutic use in the treatment of COVID-19

In a recent study, Indian researchers from the Department of Biochemistry, University of Delhi, reviewed a possible vital coalition of FoxOs – the Forkhead Box O subfamily of protein transcription factors, with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the etiological agent of COVID-19 (coronavirus disease). This review work is posted in the journal, Open Biology, published by the Royal Society.

While most of the individuals infected with SARS-CoV-2 manifest mild clinical symptoms, those with severe COVID-19 (nearly 20% of the infected) suffer acute respiratory distress syndrome, septic shock, and systemic failure. Unfortunately, this may also result in the death of the patient.

“Although physicians have been trying out various modes of treatment, clinical management of this disease is primarily symptomatic.”

The Forkhead Box O (FoxO) subfamily of transcription factors play critical functions in pulmonary homeostasis, immune and inflammatory responses, and various cellular biochemical functions. FoxOs upregulate various pro-inflammatory cytokines such as interleukin (IL)-1β and IL-9, Toll-like receptor (TLR)1 and TLR4, etc. These also primarily modulate the innate immune responses. FoxO factors are also essential for the adaptive immune functions, including maturation and differentiation of B and T lymphocytes.

Because of the vital role of FoxOs, the researchers presented the interplay of these with the SARS-CoV-2 action – which may help reduce or avoid the detrimental inflammatory upsurge post-SARS-CoV-2 infection.

FoxOs are unique master regulators of cellular inflammatory and redox responses. The FoxO family of transcription factors modulates transcriptional expression of numerous genes that are part of the host inflammation mechanism, including several interleukins, chemokines and cytokines. FoxOs also play pivotal roles in the redox homeostasis and immune response. The loss of this intricate regulatory mode of FoxOs may, thus, lead to inefficient oxidative stress response, abnormal immune cell activation and a state of exacerbated inflammation, reminiscent of a ‘cytokine storm’.

The SARS-CoV-2 is a spherical virus with spiky proteins covering its surface – the spike (S) protein forms trimeric spikes and facilitates attachment and fusion of the virus to the host receptor, ACE2 (angiotensin-converting enzyme 2). ACE2 is majorly expressed in the lung and heart tissues, and also the gut and liver.

Lung macrophages are initiated and several cytokines are elevated during a SARS-CoV-2 infection. A major cross-talk between cell-signaling molecules occurs to communicate and act on the severity of the SARS-CoV-2 infection.

The SARS-CoV-2 triggers pro-inflammatory cytokines (including interleukins, granulocyte colony-stimulating factor (gCSF), IFN-γ inducible protein, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein, and macrophage inflammatory protein), which activate the inflammatory cells – the shocking cytokine storm that causes T-cell depletion, pulmonary inflammation, lung dysfunction and multiple organ failure in the host.

“A thorough understanding of the most relevant context for introducing an anti-inflammatory therapy in juxtaposition to some sort of antiviral module may provide excellent opportunities to manage the symptoms of COVID-19.”

The researchers believe that a regime (such as antimicrobial peptide-related antivirals – lactoferrin adjuvant therapy) that may be able to curb the hyper-inflammation without altering the host’s immune efficiency for virus clearance – if FoxOs can protect against the SARS-CoV-2 virus-associated inflammatory response, simultaneously restoring redox equilibrium and favoring tissue repair.

FoxO proteins are crucial players in dynamically regulating the transcription of inflammatory factors in a context-dependent manner. The researchers elaborated the mechanisms and the numerous examples in which the FoxO family members act as both sensors of oxidative stress signals as well as regulators of the subsequent cellular response.

“Contemporary studies have unveiled that inhibitory phosphorylation of FoxOs in different immune cells like macrophages and lymphocytes are associated with inflammatory cell activation in rheumatoid arthritis and osteoarthritis patients.”

Looking at the contribution of FoxOs to thwart oxidative stress, modulate antiviral responses, inhibit pro-inflammatory responses, the researchers proposed in the review, “Whether SARS-CoV-2 abrogates the regular functions of FoxOs to execute pulmonary distress and whether restoring FoxO activity may resolve the cytokine storm are highly possible and intriguing theories that remain to be tested.”

Further, they discussed how FoxO partakes in the antiviral infection: anti-apoptotic, anti-inflammatory, a negative regulator of cellular antiviral response including excessive innate immune response, and negative regulator of NF-κB signaling. Based on previous studies, they emphasized that the FoxO3 is indispensable for mediating antiviral responses.

Because FoxO1 expression was correlated with ACE2 transcript level, the researchers implied that the FoxO factors might be tweaked to modify ACE2 availability during SARS-CoV-2 entry into the cell. They suggested exogenously modulating the FoxO for minimal ACE2 accessibility to SARS-CoV-2.

“Taken together, pharmacological activation of FoxO factors can effectively prove to be an attractive strategy to limit inflammation inflicted by NF-κB in the lungs of SARS-CoV2-infected individuals.”

The researchers depicted a schematic presentation of the potential involvement of FoxO and its downstream transcriptional network in the SARS-CoV-2 life cycle – indicating a strong possibility that SARS-CoV-2 may hijack and promote dysregulation of the FoxO factors for carrying out its infectious cycle.

The researchers ask because FoxO governs the host immune response, could it be a breakthrough in managing COVID-19? They discussed the association of FoxO, viral infection, maturation and differentiation of B cells and T cells, and memory cells – invoking these by modulating the FoxO factors as possibly one of the most lucrative modules for resisting COVID-19.

This review thus underscores the importance of FoxO proteins in the infection of and response to SARS-CoV-2 and suggests a potential outlook into the promising role of these transcription factors in restraining the pathogenesis of the novel coronavirus, the researchers write.

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.